The histogenesis of pancreatic ductal carcinoma is still controversial. Experimentally, depending on the species and carcinogen used, ductal and acinar cell tumors can be induced. The most commonly studies experimental model for pancreatic carcinoma is the N-nitrosobis (2- oxoopropyl)-amine (BOP) hamster model that in many aspects closely resembles human disease. Although our previous studies indicated in origin of the induced tumors from ductal/ductular cells,, our recent studies showed that many tumors also arise from islets, most probably from undifferentiated (stem) cells. The involvement of the islets in pancreatic carcinogenesis is associated with peripheral insulin resistance and increased levels of plasma insulin and islet amyloid polypeptide (amylin). These alterations were found by us and others to occur also in humans. Although amylin appears to be a specific marker for pancreatic cancer, we do not know at which state of pancreatic cancer development is appears. We also do not know what other or additional charges might occur early during carcinogenesis and could be used as early diagnostic markers. In this application we wish to address the following questions: 1) are human islets also the origin of pancreatic cancer? Studies will examine the role of human islets in pancreatic ductal carcinogenesis; 2) are islet alterations and tumor growth associated with hormonal changes? 3) is the development of tumors from islets dictated by the rate of islet cell replication?; 4) are tumors withi the islets developed from stem cells and, if so, can they be isolated? These questions will be examined by a series of experiments.